Summary The major goal of this project is to find out novel treatment strategies for Alzheimer?s disease (AD), a devastating neurodegenerative disorder afflicting a large number of people. A combination of genetic risk factors and environmental factors, which leads to deregulation of vulnerability genes, may be most relevant to the pathogenesis of AD. Eepigenetic mechanisms are suggested to be central to the manifestation of pathological gene alteration and might act as a bottleneck to mediate gene-environment interactions relevant to disease progression. Using the transgenic mice carrying 5 familial AD (5xFAD) mutations on human amyloid precursor protein and presenilin 1, we have found that glutamatergic transmission is significantly diminished in cortical pyramidal neurons of 5xFAD mice (5-6 months), which is accompanied by the loss of AMPA and NMDA receptor transcription and expression. Moreover, the repressive histone methylation, which is linked to gene silencing, is significantly elevated in 5xFAD mice. We hypothesize that abnormal epigenetic regulation of glutamate receptor transcription resulting from aberrant histone methylation underlies the synaptic and cognitive deficits in AD, and targeting the histone methyltransferases provides a novel strategy for AD treatment. To test this hypothesis, three specific aims will be addressed. Aim 1. To identify key epigenetic mechanisms causing the synaptic and cognitive deficits in AD mouse models. We will examine the alteration of histone methyltransferases (HMTs) and histone methylation at the promoter regions of glutamate receptors in AD mouse models with amyloid plaques or neurofibrillary tangles. Aim 2. To investigate the rescue of synaptic and cognitive deficits by targeting key epigenetic molecules in AD mouse models. We will examine whether inhibiting the euchromatic histone methyltransferases, EHMT1 and EHMT2, which repress transcription, could lead to the recovery of synaptic function and the amelioration of cognitive impairment in AD mice. Aim 3. To examine the molecular alteration and treatment strategy in human stem cell-derived neurons from AD patients. To find out whether the epigenetic treatment strategy found in AD mouse models might also work in AD patients, we will take advantage of the innovative stem-cell technology to examine human neurons differentiated from induced pluripotent stem cells (iPSC) derived from skin fibroblasts. We will examine the alterations of glutamate receptor transcription and function, as well as histone methylation, in human neurons from AD patients, and the capability of EHMT1/2 inhibitors to reverse synaptic deficits. Results gained from this project will help to define disease-specific epigenetic signatures and identify corresponding therapeutic strategies for AD.